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Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide
M. Dawidowski, M. Król, B. Szulczyk, A. Chodkowski, P. Podsadni, P. Konopelski, M. Ufnal, P. Szuberski, MZ. Wróbel, Y. Zhang, A. El Harchi, JC. Hancox, D. Jarkovska, E. Mistrova, J. Sviglerova, M. Štengl, GM. Popowicz, J. Turło
Bioorganic chemistry.
2020 ;
98 (-) :
103717.
[pub] 20200305
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Persistent link
https://www.medvik.cz/link/bmc21012625
Grant support
PG/12/69/29784
British Heart Foundation - United Kingdom
PG/14/61/31015
British Heart Foundation - United Kingdom
- MeSH
- Acetamides administration & dosage chemistry therapeutic use MeSH
- Anticonvulsants administration & dosage chemistry therapeutic use MeSH
- Disopyramide administration & dosage chemistry therapeutic use MeSH
- Electroshock MeSH
- Injections, Intraperitoneal MeSH
- Injections, Subcutaneous MeSH
- Rats MeSH
- Molecular Structure MeSH
- Mice MeSH
- Pentylenetetrazole administration & dosage MeSH
- Rats, Wistar MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Seizures chemically induced drug therapy MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
References provided by Crossref.org
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- $a A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
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